Parathyroid hormone and analogues

Whitfield J, Morley P, Willick G. The parathyroid hormone, its fragments and analogues—potent bone-builders for treating osteoporosis. Expert Opin Investig Drugs 2000 9(6) 1293-315. 

It is now well established that l,25-(OH)2D3 is the active hormonal form of vitamin D3 [32], The production of l,25-(OH)2D3 in the kidney is regulated by dietary calcium and phosphate and also by changes in serum calcium and parathyroid hormone, which clearly highlight the hormonal nature of this compound. Functionally, the three classical actions of l,25-(OH)2D3 are to stimulate intestinal calcium and independently phosphate absorption, the mobilization of calcium from bone, and increase renal reabsorption of calcium. The focus of this review will be to explore the most recent concepts of vitamin D in regard to its metabolism and physiology, and with respect to the medicinal applications of vitamin D3 metabolites and analogues. 

Further evidence that C-25 and C-l hydroxylation are the activation steps of vitamin D3, and that C-24/C-23 and C-23/C-26-lactone metabolic conversions do not produce physiologically important products is with the use of side-chain fluoridated analogues of 25-OH-D3 [87, 88], Studies with these analogues were prompted by assertions that 24-hydroxylated or lactone metabolites are involved or required for such biological actions as mineralization of bone [89], suppression of parathyroid hormone secretion [90], cartilage metabolism [91], and embryonic development in the chick [92]. It is well established that plasma 24,25-(OH)2D3 concentrations (2-5 ng/ml) are approximately 50 times greater than those of l,25-(OH)2D3. Even so,... 

Of 19 chronic hemodialysis patients taking a combination of alfacalcidol and calcitriol for 12 months, six had increased bone resorption, six had reduced bone resorption, and seven had no change. Histologically documented aggravation of hyperparathyroidism was associated with a statistically significant increase in plasma concentrations of phosphate and parathyroid hormone. The administration of vitamin D analogues may therefore be either beneficial or noxious depending on whether or not induced hyperphosphatemia is adequately prevented (55). 

M. Coltrera, M. Rosenblatt, and J. T. Potts, Jr., Analogues of parathyroid hormone containing D-amino acids Evaluation of biological activity and stability, Biochemistry, 19, 4380-4385 (1980). 

Tumorigenidty Osteosarcoma is postulated as a potential adverse reaction to parathyroid hormone analogues, based on animal studies, and another case has been reported in a 67-year-old man who took teriparatide 20 micrograms/day subcutaneously for 2 months, 7 years after a course of radiotherapy for recurrent prostate cancer [65 ]. However, the osteosarcoma occurred within the field of previous radiotherapy and the time course suggested that the osteosarcoma may have been present before teriparatide administration. The authors noted that 430 000 patients have been treated with teriparatide for osteoporosis and that there have been only two reported cases of osteosarcoma, which is consistent with the expected population incidence of 4-5 per million. However, the effect of teriparatide on the growth of an undiagnosed osteosarcoma is unknown, and so teriparatide should be used with caution in patients who have had previous radiotherapy. 

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